Phenylephrine is a pharmacological active substance in the sympathomimetics group and possesses agonistic activity on the α1-adrenergic receptor. Apart from the missing 3-hydroxyl group it is structurally the same as adrenaline and mainly finds application as a local vasoconstrictor. As the active substance in nasal drops it therefore has a decongestant action on the mucosae. In eye drops it also has mydriatic action, and thus leads to dilation of the pupils.
The production of phenylephrine is already described in the literature. In addition to the numerous methods for production of the desired product as racemate and then transforming it to the product by cleavage with a suitable chiral auxiliary agent, the methods of stereoselective synthesis are to be regarded as preferable, as it is then possible to avoid the uneconomic destruction of the resultant 50% of incorrect enantiomer.
The methods of production of L-phenylephrine hydrochloride known from the prior art include the asymmetric hydrogenation of the prochiral N-benzy-N-methyl-2-amino-m-benzyloxyacetophenone hydrochloride according to Tetrahedron Letters 30 (1989), 367-370, or Chem. Pharm. Bull. 43 (5) (1995) 738-747.
Achiwa et al. describe in Tetrahedron Letters 30 (1989), 367-370 the asymmetric hydrogenation of 3-benzyloxy-2-(N-benzyl-N-methyl)-aminoacetophenone hydrochloride as substrate with hydrogen in the presence of [Ph(COD)Cl]2/(2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-methyl)-N-methyl-aminopyrrolidine as catalyst. Immediately after filtration and concentration of the reaction mixture by evaporation, the benzyl nitrogen protective group is cleaved and phenylephrine is obtained as product. Along with the L-enantiomer, the D-enantiomer is produced as impurity in a proportion of at least 7.5% (85% ee). For the reaction, the catalyst must be used in a molar ratio of 1:2000 relative to the substrate. The drawback of this method is essentially that the L-phenylephrine obtained cannot be purified economically to a purity of at least 98% ee, which is required for use as a medicinal product.
In Chem. Pharm. Bull. 43 (5) (1995) 738-747, a molar ratio of substrate to catalyst of about 1000:1 is stated to be preferable for the asymmetric hydrogenation. However, despite the use of quite large amounts of catalyst in the asymmetric reaction step, the product cannot be produced in sufficient purity as L-enantiomer for pharmaceutical purposes without expensive purification procedures, but can only be obtained as a mixture with a relatively high proportion of D-enantiomer as impurity. The relatively long reaction time of the asymmetric hydrogenation step of approx. 20 hours also represents, for the production of L-phenylephrine on an industrial scale, a reaction step that is expensive and costly in terms of equipment, with a safety risk that cannot be ignored.
The method described in WO 00/43345 fulfills some of the stated conditions for an economically meaningful production of L-phenylephrine hydrochloride but here too the use of protective groups is still required, so that the method becomes less economical. Furthermore, even according to this method, in the stereoselective step the desired product is only obtained at 93% ee, so that once again it must be followed by expensive purification.